Dr. Bailey-Wilson has been working for over 20 years to detect genetic risk factors for lung cancer and possible gene-gene and/or gene-environment interactions. The purpose of this study is to identify a gene or genes that contribute to lung cancer susceptibility. In this fiscal year, family data have been collected in Louisiana. Data collection is expected to continue for several more years. Dr. Bailey-Wilson is a founder of the Genetic Epidemiology of Lung Cancer Consortium (GELCC) for the purpose of obtaining additional family data from a large group of collaborative investigators. A paper presenting GELCC results has been published in this fiscal year. About 60 families were genotyped for GWS markers at the Center for Inherited Disease Research (CIDR) and the first genome-wide significant linkage of a lung cancer susceptibility locus on chromosome 6q was published by us last year. A paper characterizing the effect of smoking in individuals predicted to be carriers of this 6q locus is in preparation. In this fiscal year, we have sequenced almost 100 candidate loci in this region and follow-up of these results is ongoing. A second set of families has been genotyped for the same GWS markers and analyses are ongoing. Dr. Bailey-Wilson and Dr. Doan have also applied their new propensity score method for including environmental risk factor data into non-parametric analyses (in LODPAL) to the original GWS data and a paper is in preparation. Another major aim of Dr. Bailey-Wilson?s research is to determine genetic risk factors in families with human prostate cancer. Papers published previously by our large group of collaborators have shown evidence of PRCA susceptibility genes in regions of chromosomes 1, 3p, 11q, 8 and X. These results have been followed up by intensive linkage analyses of additional families to markers in these regions and in other regions that showed some mild evidence of linkage in the initial genome scans. Previously, our group identified mutations in the ribonuclease-L (RNASEL) gene as being the locus in our chromosome 1 linkage region causing increased risk to prostate cancer and showed evidence that mutations in the MSR1 gene on chromosome 8 plays a role in prostate cancer risk. Families have been genotyped from several regions of the United States, Finland, Iceland and Sweden. Dr. Bailey-Wilson's group is currently analyzing the Finnish and African-American data. We have joined the International Prostate Cancer Genetics Consortium (ICPCG) to try to localize prostate cancer loci more rapidly. Two meta-analysis papers were published by this group this year and another is in preparation. Dr. Bailey-Wilson is in charge of the Chromosome X meta-analysis. A paper detailing evidence of a significant association in our Finnish families to a narrow region on chromosome X has been published in this fiscal year. A linkage genome-wide scan of families from Finland, Sweden, and the U.S., including a significant number of African-American families from the African American Hereditary Prostate Cancer Consortium (AAHPC), of which Dr. Bailey-Wilson is a member, is ongoing in this fiscal year and will continue into the next year. A paper detailing the results of this genome wide scan in the Finnish families and another with results of a metaanalysis of several of these datasets have been published in the last fiscal year. Fine mapping markers were genotyped for the Finnish dataset to follow uo suggestive linkages, resulting in a paper published this year presenting strong evidence for a locus on chromosome 3p. We will continue to pursue evidence of a major locus in this region in these families. A new set of 43 extended Finnish prostate cancer pedigrees have been collected, power studies have been performed and genotyping for a genome wide scan has been started. Analyses will be performed in the next fiscal year. The GWS analysis of the African-American families described above has been completed and a paper presenting the results has been submitted. Another paper detailing the clinical characteristics of the African-American men in this dataset was published this year, as was a paper showing an association between a nonsense mutation in the gene EphB2 is associated with increased prostate cancer risk in African-American men. A linkage meta-analysis is now underway to combine our African-American families from the AAHPC with those available from the ICPCG in order to increase power to detect loci that are of particular importance in this racial group. A collaborative linkage study of breast cancer families that are not segregating mutations at either the BRCA1 or BRCA2 loci is ongoing. We are working with collaborators in Finland to follow-up candidate regions from our previous genome-wide linkage studies. Additional genotyping of SNP markers in several of these regions has been performed and association analyses are ongoing. A new dataset, in collaboration with Dr. Rachel Ellsworth of the Windber Research Institute, and Drs. Henry Lynch and Patrice Watson of Creighton University, is now being studied. In this study, we are examining families with known mutations in BRCA1 and BRCA2 loci to attempt to detect modifier loci and gene-gene interactions. Genotyping for GWS markers has been completed in this fiscal year and these data will be analyzed in the next fiscal year. As an adjunct to the family-based studies of prostate and breast cancer described above, Dr. Bailey-Wilson is collaborating with Drs. Trent and Carpten of Tranlational Genomics, Drs. Cristina Leske and Barbara Nemesure of State University of New York at Stony Brook and Drs. Anselm Hennis and Lyndon Waterman of the University of the West Indies, in Barbados, on a study of the genetic epidemiology of prostate cancer and breast cancer in Barbados. These cancers occur at very high rates in the Barbadian population. Dr. Hennis' joint appointments in New York and Barbados have expedited this study. The pilot phase of a large case-control study is underway and a small adjunct family study is also being piloted. Questionnaires, study protocols and consent forms have been developed and are currently being used in Barbados, funded by a contract from NHGRI. This pilot data collection phase is expected to last for one more year, to be followed by the very large study. Dr. Bailey-Wilson is now the Project Officer for the data collection pilot study contract. Data collection is proceeding on schedule. The first analyses of these pilot data were performed this year; SNP loci were genotyped in the BRCA1 locus to determine if association to common polymorphisms at this locus could explain any large proportion of the breast cancer risk in this population. A manuscript is in preparation presenting these results. A collaborative linkage study of melanoma families that are not linked to known melanoma loci is ongoing. A genome wide scan of these samples yielded significant evidence of linkage of early-onset melanoma to one region of the genome at chromosome 1p22. Approximately 50 additional families from the Melanoma Consortium have been collected this year. Genotyping to exclude linkage to known loci is in progress. Appropriate families will be typed for a genome wide scan by CIDR and data will be merged with the data from the original scan to identify novel regions of interest. We continue to do follow up work in the 1p22 region identified in early onset cutaneous melanoma families. We have selected ~ 400 SNP markers to be genotyped in this region for a fine-mapping study. These data will be analyzed by Dr. Bailey-Wilson's group, using both linkage and association methods. In families that segregate both ocular and cutaneous melanoma we have typed 50 microsatellite and 1500 SNP markers in 3 regions. These data have been analyzed in this fiscal year and a manuscript is in preparation.